October 13, 2009

Case Western Reserve University School of Medicine Researchers Receive $1.25M from NIMH to Study Schizophrenia

Study to use pluripotent stem cells (iPS) to provide insight into this complex disease

Case Western Reserve University School of Medicine has received $1.25 million from the National Institutes of Mental Health, part of the National Institutes of Health, to study schizophrenia from an interdisciplinary standpoint. The grant, to be funded over four years, includes three project investigators from three different practice areas.

The scientists, Paul Tesar, PhD, Assistant Professor in the Department of Genetics and Center for Stem Cell and Regenerative Medicine, responsible for the stem cell portion; Robert Miller, PhD, Vice Dean for Research and the Allen C. Holmes Professor of Neurological Diseases, responsible for the neural portion; and Robert Findling, MD, the Rocco L. Motto, M.D. Professor of Child & Adolescent Psychiatry, responsible for the schizophrenia/mental health portion, will work together to provide a detailed characterization of brain cell function in adolescent patients afflicted with schizophrenia.

Schizophrenia is a serious psychiatric condition with a worldwide prevalence of approximately one percent. Individuals with schizophrenia experience very severe symptoms and are at an increased risk for suicide, unemployment, permanent disability, and homelessness. Affected adolescents experience even more severe symptoms, tend to be more chronically dysfunctional, suffer from greater cognitive impairments, and may have greater functional and social disability than those with adult-onset schizophrenia.

"Unfortunately, the cause of schizophrenia is currently unknown and the molecular- and cellular-based mechanisms that contribute to schizophrenia remain undefined," said Miller. "However, there is a growing body of evidence to suggest that schizophrenia is a neurodevelopmental disorder with genetics being a key risk factor for illness expression."

Although schizophrenia has classically been considered a neurotransmitter-based disorder, there is emerging evidence that dysregulation of oligodendrocyte function is a key contributor to the psychiatric symptoms seen in afflicted patients. Oligodendrocytes produce an insulating coating called myelin that surrounds nerve cells. Myelin is required for the proper conduction of signals along the nerves. Without the proper production of myelin by the oligodendrocytes, communication within the brain or between the brain and other parts of the body is disrupted. This causes dysfunction. To understand the contribution of oligodendrocyte function to schizophrenia requires a robust source of oligodedrocytes from schizophrenia patients.

"We have established an interdisciplinary team that combines strengths in clinical schizophrenia research, neural differentiation and function, as well as pluripotent stem cells (having the ability to differentiate into all cell types of the human body) to learn about the cellular and molecular dysfunction that contributes to schizophrenia," said Tesar. "This innovative approach will offer novel insights into the mechanisms that contribute to this complex, devastating disease."

The researchers will begin by developing a cell-based system whereby oligodendrocytes from afflicted individuals can be functionally assayed to interrogate the molecular mechanisms underlying schizophrenia. Since oligodendrocytes cannot be harvested directly from the brains of living patients, the researchers will take skin samples from volunteers with schizophrenia and reprogram them back to a primitive, pluripotent state. These reprogrammed cells, called induced pluripotent stem (iPS) cells, are a genetic match to each patient-donor and capable to be turned into all cell types of the adult body, including oligodedrocytes. The iPS cells provide, for the first time, the ability to produce a large number of patient-specific oligodendrocytes. The iPS cell-derived oligodendrocytes from patient-volunteers with schizophrenia will be compared to those from unaffected control volunteers. In doing so, the researchers hope to provide a clear understanding of the cellular and molecular deficiencies in oligodendrocytes from schizophrenia patients.

"We hope to understand the underlying cause of schizophrenia in much greater depth. If we can decipher why the cells aren’t functioning properly, we may be able to develop treatments that can restore function to vulnerable patients suffering from schizophrenia," said Findling.

NOTE: The guardians of adolescents interested in becoming a potential volunteer for this study—both for the control group and for the schizophrenia patient group, can call 216.844.3922.

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